A multicentre validation study of the diagnostic value of plasma neurofilament light

Nicholas J. Ashton; Shorena Janelidze; Ahmad Al Khleifat; Antoine Leuzy; Emma L. van der Ende; Thomas K. Karikari; Andrea L. Benedet; Tharick A. Pascoal; Alberto Lleó; Lucilla Parnetti; Daniela Galimberti; Laura Bonanni; Andrea Pilotto; Alessandro Padovani; Jan Lycke; Lenka Novakova; Markus Axelsson; Latha Velayudhan; Gil D. Rabinovici; Bruce Miller; Carmine Pariante; Naghmeh Nikkheslat; Susan M. Resnick; Madhav Thambisetty; Michael Schöll; Gorka Fernández-Eulate; Francisco J. Gil-Bea; Adolfo López de Munain; Ammar Al-Chalabi; Pedro Rosa-Neto; Andre Strydom; Per Svenningsson; Erik Stomrud; Alexander Santillo; Dag Aarsland; John C. van Swieten; Sebastian Palmqvist; Henrik Zetterberg; Kaj Blennow; Abdul Hye; Oskar Hansson

doi:10.1038/s41467-021-23620-z

A multicentre validation study of the diagnostic value of plasma neurofilament light

Nicholas J. Ashton^*, Shorena Janelidze, Ahmad Al Khleifat, Antoine Leuzy, Emma L. van der Ende, Thomas K. Karikari, Andrea L. Benedet, Tharick A. Pascoal, Alberto Lleó, Lucilla Parnetti, Daniela Galimberti, Laura Bonanni, Andrea Pilotto, Alessandro Padovani, Jan Lycke, Lenka Novakova, Markus Axelsson, Latha Velayudhan, Gil D. Rabinovici, Bruce MillerCarmine Pariante, Naghmeh Nikkheslat, Susan M. Resnick, Madhav Thambisetty, Michael Schöll, Gorka Fernández-Eulate, Francisco J. Gil-Bea, Adolfo López de Munain, Ammar Al-Chalabi, Pedro Rosa-Neto, Andre Strydom, Per Svenningsson, Erik Stomrud, Alexander Santillo, Dag Aarsland, John C. van Swieten, Sebastian Palmqvist, Henrik Zetterberg, Kaj Blennow, Abdul Hye, Oskar Hansson^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › Academic › peer-review

122 Citations (Scopus)

Abstract

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King’s College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

Original language	English
Article number	3400
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23620-z
Publication status	Published - 7 Jun 2021

Bibliographical note

Funding Information:
This study is independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. This project was partly funded by the MND Association and the Wellcome Trust. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND—www.jpnd.eu (United Kingdom, Medical Research Council MR/L501529/1, MR/ R024804/1) and Economic and Social Research Council (ES/L008238/1)). A.A.C. is an NIHR Senior Investigator and receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King’s College London. The work leading up to this publication was funded by the European Community’s Health Seventh Framework Program (FP7/2007–2013; grant agreement number 259867) and Horizon 2020 Program (H2020-PHC-2014-two-stage; grant agreement number 633413). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement 772376 - EScORIAL. Work at Lund University was supported by the European Research Council, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Marianne and Marcus Wallenberg Foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, The Parkinson Foundation of Sweden, The Parkinson Research Foundation, the Skåne University Hospital Foundation, and the Swedish federal government under the ALF agreement. Doses of 18F-flutemetamol injection were sponsored by GE Healthcare. We are grateful to participants in the BLSA for their invaluable contribution. This study was supported in part by the intramural research program of the National Institute on Aging (NIA), National Institutes of Health (NIH). N.J.A. is funded by the Wallenburg Centre for Molecular and Translational, Swedish Alzheimer Foundation (Alzheimerfonden), the Swedish Dementia Foundation (Demensfonden), Hjärnfonden (#FO2020-0241) and Gamla Tjänarinnor. A.A.K is funded by The Motor Neurone Disease Association (MNDA) and NIHR Maudsley Biomedical Research Centre. G.F.-E. was supported by the neuromuscular diseases (GEEN) of the Spanish Society of Neurology (SEN) and the SEN itself. A.S. has received grants from a Wellcome Trust Strategic Award (grant number 098330/Z/12/Z conferred upon The London Down Syndrome (LonDownS) Consortium), and the UK Medical Research Council (Medical Research Council grants MRC S011277/1, MR/S005145/1 via Centres of Excellence in Neurodegeneration research, and MR/R024901/1 via JPND) and the work was further supported by the National Institute for Health Research networks (mental health, dementias, and neurology) and participating NHS trusts. P.S. is a Wal-lenberg Clinical Scholar and also funded by CBD solutions, Stockholm City Council, Swedish Foundation for Strategic Research and Van Geest Foundation. H.Z. is a Wal-lenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931) and the UK Dementia Research Institute at UCL. K.B. is supported by the Torsten Söderberg Foundation, Stockholm, Sweden. We would also like to acknowledge Lieke H Meeter in contributing to the collection of the samples.

Publisher Copyright:
© 2021, The Author(s).

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10.1038/s41467-021-23620-z

Cite this

Ashton, N. J., Janelidze, S., Al Khleifat, A., Leuzy, A., van der Ende, E. L., Karikari, T. K., Benedet, A. L., Pascoal, T. A., Lleó, A., Parnetti, L., Galimberti, D., Bonanni, L., Pilotto, A., Padovani, A., Lycke, J., Novakova, L., Axelsson, M., Velayudhan, L., Rabinovici, G. D., ... Hansson, O. (2021). A multicentre validation study of the diagnostic value of plasma neurofilament light. Nature Communications, 12(1), [3400]. https://doi.org/10.1038/s41467-021-23620-z

@article{7adc542d7eb9411797788cfea0840547,

title = "A multicentre validation study of the diagnostic value of plasma neurofilament light",

abstract = "Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King{\textquoteright}s College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.",

author = "Ashton, {Nicholas J.} and Shorena Janelidze and {Al Khleifat}, Ahmad and Antoine Leuzy and {van der Ende}, {Emma L.} and Karikari, {Thomas K.} and Benedet, {Andrea L.} and Pascoal, {Tharick A.} and Alberto Lle{\'o} and Lucilla Parnetti and Daniela Galimberti and Laura Bonanni and Andrea Pilotto and Alessandro Padovani and Jan Lycke and Lenka Novakova and Markus Axelsson and Latha Velayudhan and Rabinovici, {Gil D.} and Bruce Miller and Carmine Pariante and Naghmeh Nikkheslat and Resnick, {Susan M.} and Madhav Thambisetty and Michael Sch{\"o}ll and Gorka Fern{\'a}ndez-Eulate and Gil-Bea, {Francisco J.} and {L{\'o}pez de Munain}, Adolfo and Ammar Al-Chalabi and Pedro Rosa-Neto and Andre Strydom and Per Svenningsson and Erik Stomrud and Alexander Santillo and Dag Aarsland and {van Swieten}, {John C.} and Sebastian Palmqvist and Henrik Zetterberg and Kaj Blennow and Abdul Hye and Oskar Hansson",

note = "Funding Information: This study is independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. This project was partly funded by the MND Association and the Wellcome Trust. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND—www.jpnd.eu (United Kingdom, Medical Research Council MR/L501529/1, MR/ R024804/1) and Economic and Social Research Council (ES/L008238/1)). A.A.C. is an NIHR Senior Investigator and receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. The work leading up to this publication was funded by the European Community{\textquoteright}s Health Seventh Framework Program (FP7/2007–2013; grant agreement number 259867) and Horizon 2020 Program (H2020-PHC-2014-two-stage; grant agreement number 633413). This project has received funding from the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement 772376 - EScORIAL. Work at Lund University was supported by the European Research Council, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Marianne and Marcus Wallenberg Foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson{\textquoteright}s disease) at Lund University, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, The Parkinson Foundation of Sweden, The Parkinson Research Foundation, the Sk{\aa}ne University Hospital Foundation, and the Swedish federal government under the ALF agreement. Doses of 18F-flutemetamol injection were sponsored by GE Healthcare. We are grateful to participants in the BLSA for their invaluable contribution. This study was supported in part by the intramural research program of the National Institute on Aging (NIA), National Institutes of Health (NIH). N.J.A. is funded by the Wallenburg Centre for Molecular and Translational, Swedish Alzheimer Foundation (Alzheimerfonden), the Swedish Dementia Foundation (Demensfonden), Hj{\"a}rnfonden (#FO2020-0241) and Gamla Tj{\"a}narinnor. A.A.K is funded by The Motor Neurone Disease Association (MNDA) and NIHR Maudsley Biomedical Research Centre. G.F.-E. was supported by the neuromuscular diseases (GEEN) of the Spanish Society of Neurology (SEN) and the SEN itself. A.S. has received grants from a Wellcome Trust Strategic Award (grant number 098330/Z/12/Z conferred upon The London Down Syndrome (LonDownS) Consortium), and the UK Medical Research Council (Medical Research Council grants MRC S011277/1, MR/S005145/1 via Centres of Excellence in Neurodegeneration research, and MR/R024901/1 via JPND) and the work was further supported by the National Institute for Health Research networks (mental health, dementias, and neurology) and participating NHS trusts. P.S. is a Wal-lenberg Clinical Scholar and also funded by CBD solutions, Stockholm City Council, Swedish Foundation for Strategic Research and Van Geest Foundation. H.Z. is a Wal-lenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931) and the UK Dementia Research Institute at UCL. K.B. is supported by the Torsten S{\"o}derberg Foundation, Stockholm, Sweden. We would also like to acknowledge Lieke H Meeter in contributing to the collection of the samples. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jun,

day = "7",

doi = "10.1038/s41467-021-23620-z",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Ashton, NJ, Janelidze, S, Al Khleifat, A, Leuzy, A, van der Ende, EL, Karikari, TK, Benedet, AL, Pascoal, TA, Lleó, A, Parnetti, L, Galimberti, D, Bonanni, L, Pilotto, A, Padovani, A, Lycke, J, Novakova, L, Axelsson, M, Velayudhan, L, Rabinovici, GD, Miller, B, Pariante, C, Nikkheslat, N, Resnick, SM, Thambisetty, M, Schöll, M, Fernández-Eulate, G, Gil-Bea, FJ, López de Munain, A, Al-Chalabi, A, Rosa-Neto, P, Strydom, A, Svenningsson, P, Stomrud, E, Santillo, A, Aarsland, D, van Swieten, JC, Palmqvist, S, Zetterberg, H, Blennow, K, Hye, A & Hansson, O 2021, 'A multicentre validation study of the diagnostic value of plasma neurofilament light', Nature Communications, vol. 12, no. 1, 3400. https://doi.org/10.1038/s41467-021-23620-z

TY - JOUR

T1 - A multicentre validation study of the diagnostic value of plasma neurofilament light

AU - Ashton, Nicholas J.

AU - Janelidze, Shorena

AU - Al Khleifat, Ahmad

AU - Leuzy, Antoine

AU - van der Ende, Emma L.

AU - Karikari, Thomas K.

AU - Benedet, Andrea L.

AU - Pascoal, Tharick A.

AU - Lleó, Alberto

AU - Parnetti, Lucilla

AU - Galimberti, Daniela

AU - Bonanni, Laura

AU - Pilotto, Andrea

AU - Padovani, Alessandro

AU - Lycke, Jan

AU - Novakova, Lenka

AU - Axelsson, Markus

AU - Velayudhan, Latha

AU - Rabinovici, Gil D.

AU - Miller, Bruce

AU - Pariante, Carmine

AU - Nikkheslat, Naghmeh

AU - Resnick, Susan M.

AU - Thambisetty, Madhav

AU - Schöll, Michael

AU - Fernández-Eulate, Gorka

AU - Gil-Bea, Francisco J.

AU - López de Munain, Adolfo

AU - Al-Chalabi, Ammar

AU - Rosa-Neto, Pedro

AU - Strydom, Andre

AU - Svenningsson, Per

AU - Stomrud, Erik

AU - Santillo, Alexander

AU - Aarsland, Dag

AU - van Swieten, John C.

AU - Palmqvist, Sebastian

AU - Zetterberg, Henrik

AU - Blennow, Kaj

AU - Hye, Abdul

AU - Hansson, Oskar

N1 - Funding Information: This study is independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. This project was partly funded by the MND Association and the Wellcome Trust. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND—www.jpnd.eu (United Kingdom, Medical Research Council MR/L501529/1, MR/ R024804/1) and Economic and Social Research Council (ES/L008238/1)). A.A.C. is an NIHR Senior Investigator and receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King’s College London. The work leading up to this publication was funded by the European Community’s Health Seventh Framework Program (FP7/2007–2013; grant agreement number 259867) and Horizon 2020 Program (H2020-PHC-2014-two-stage; grant agreement number 633413). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement 772376 - EScORIAL. Work at Lund University was supported by the European Research Council, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Marianne and Marcus Wallenberg Foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, The Parkinson Foundation of Sweden, The Parkinson Research Foundation, the Skåne University Hospital Foundation, and the Swedish federal government under the ALF agreement. Doses of 18F-flutemetamol injection were sponsored by GE Healthcare. We are grateful to participants in the BLSA for their invaluable contribution. This study was supported in part by the intramural research program of the National Institute on Aging (NIA), National Institutes of Health (NIH). N.J.A. is funded by the Wallenburg Centre for Molecular and Translational, Swedish Alzheimer Foundation (Alzheimerfonden), the Swedish Dementia Foundation (Demensfonden), Hjärnfonden (#FO2020-0241) and Gamla Tjänarinnor. A.A.K is funded by The Motor Neurone Disease Association (MNDA) and NIHR Maudsley Biomedical Research Centre. G.F.-E. was supported by the neuromuscular diseases (GEEN) of the Spanish Society of Neurology (SEN) and the SEN itself. A.S. has received grants from a Wellcome Trust Strategic Award (grant number 098330/Z/12/Z conferred upon The London Down Syndrome (LonDownS) Consortium), and the UK Medical Research Council (Medical Research Council grants MRC S011277/1, MR/S005145/1 via Centres of Excellence in Neurodegeneration research, and MR/R024901/1 via JPND) and the work was further supported by the National Institute for Health Research networks (mental health, dementias, and neurology) and participating NHS trusts. P.S. is a Wal-lenberg Clinical Scholar and also funded by CBD solutions, Stockholm City Council, Swedish Foundation for Strategic Research and Van Geest Foundation. H.Z. is a Wal-lenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931) and the UK Dementia Research Institute at UCL. K.B. is supported by the Torsten Söderberg Foundation, Stockholm, Sweden. We would also like to acknowledge Lieke H Meeter in contributing to the collection of the samples. Publisher Copyright: © 2021, The Author(s).

PY - 2021/6/7

Y1 - 2021/6/7

N2 - Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King’s College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

AB - Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King’s College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

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U2 - 10.1038/s41467-021-23620-z

DO - 10.1038/s41467-021-23620-z

M3 - Article

C2 - 34099648

AN - SCOPUS:85107306441

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3400

ER -

A multicentre validation study of the diagnostic value of plasma neurofilament light

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